Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition

Gao, Lei; Hu, Yong; Tian, Ye; Fan, Zhenzhen; Wang, Kun; Li, Hongdan; Zhou, Qian; Zeng, Guandi; Hu, Xin; Yu, Lei; Zhou, Shuhua; Tong, Xinyuan; Huang, Hsin‐Yi; Chen, Haiquan; Liu, Qingsong; Liu, Wanting; Zhang, Gong; Zeng, Mu‐Sheng; Zhou, Guang‐Biao; He, Qing‐Yu; Ji, Hongbin; Chen, Liang

doi:10.1038/s41467-019-09295-7

Cited by 52 publications

(41 citation statements)

References 64 publications

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“…This implies that finding a targeting therapy for GATA4 deficient HCC patients is of paramount clinical significance. Of note, tumor suppressive function of GATA4 was recently reported in other cancers 39.…”

Section: Discussionmentioning

confidence: 84%

A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients

Zhou

Liu

et al. 2020

Theranostics

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Rationale: Effective targeting therapies are limited in Hepatocellular carcinoma (HCC) clinic. Characterization of tumor suppressor genes (TSGs) and elucidation their signaling cascades could shed light on new strategies for developing targeting therapies for HCC.Methods: We checked genome-wide DNA copy number variation (CNV) of HCC samples, focusing on deleted genes for TSG candidates. Clinical data, in vitro and in vivo data were collected to validate the tumor suppressor functions.Results: Focal deletion of GATA4 gene locus was the most prominent feature across all liver cancer samples. Ectopic expression of GATA4 resulted in senescence of HCC cell lines. Mechanistically, GATA4 exerted tumor suppressive role by orchestrating the assembly of a tumor suppressor enhancing module: GATA4 directly bound and potently inhibited the mRNA transcription activity of β-catenin; meanwhile, β-catenin was recruited by GATA4 to promoter regions and facilitated transcription of GATA4 target genes, which were TSGs per se. Expression of GATA4 was effective to shrink GATA4-deficient HCC tumors in vivo. We also showed that β-catenin inhibitor was capable of shrinking GATA4-deficient tumors.Conclusions: Our study unveiled a previously unnoticed tumor suppressor enhancing module assembled by ectopically expressed GATA4 in HCC cells and denoted a therapeutic opportunity for GATA4 deficient HCC patients. Our study also presented an interesting case that an oncogenic transcription factor conditionally functioned as a tumor suppressor when recruited by a TSG transcription factor.

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Section: Discussionmentioning

confidence: 84%

A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients

Zhou

Liu

et al. 2020

Theranostics

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“…Tet-Kras* mice develop lung cancers after feeding with Dox diet for around 3 months, but remain lung cancer free if fed with normal diet 31 . We then infected lung epithelial compartment of Tet-Kras* mice with lentivirus harboring Tet-CLU cassette through intra-nasal instillation (designated Tet-Kras*+C mice) following our earlier protocol 32 , such that virus-infected mice started to express Kras G12D and CLU in lung epithelial cells when fed with Dox diet ( Figure S1 T). In parallel, we also generated a cohort of Tet-Kras* mice infected with lentivirus harboring Tet-mCherry (serving as Control, designated Tet-Kras*+m) ( Figure S1 T).…”

Section: Resultsmentioning

confidence: 99%

Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity

Chen¹,

Fan²,

Dou³

et al. 2020

Theranostics

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Purpose: Clinical success of precision medicine is severely limited by de novo or acquired drug resistance. It remains a clinically unmet need to treat these patients. Tumor suppressor genes (TSGs) play a critical role in tumorigenesis and impact the therapeutic effect of various treatments. Experimental Design: Using clinical data, in vitro cell line data and in vivo mouse model data, we revealed the tumor suppressive role of Clusterin in lung cancer. We also delineated the signaling cascade elicited by loss of function of CLU in NSCLC cells and tested precision medicine for CLU deficient lung cancers. Results: CLU is a potent and clinically relevant TSG in lung cancer. Mechanistically, CLU inhibits TGFBR1 to recruit TRAF6/TAB2/TAK1 complex and thus inhibits activation of TAK1- NF-κB signaling axis. Lung cancer cells with loss of function of CLU show exquisite sensitivity to TAK1 inhibitors. Importantly, we show that a significant portion of Kras mutation positive NSCLC patients are concurrently deficient of CLU and that TAK1 kinase inhibitor synergizes with existing drugs to treat this portion of lung cancers patients. Conclusions: Combinational treatment with TAK1 inhibitor and MEK1/2 inhibitor effectively shrank Kras mutation positive and CLU deficient NSCLC tumors. Moreover, we put forward a concept that loss of function of a TSG rewires signaling network and thereby creates an Achilles' heel in tumor cells which could be exploited in precision medicine.

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“…Interestingly, we found deletions of GATA4 and LRP1B in a patient who failed to response to olaparib. GATA4 and LRP1B were tumor suppressor genes 32,64 , which might be related to the resistance of olaparib. However, only one patient tested is not enough to support this deduce, and more relevant cases still needed for further research.…”

Section: Discussionmentioning

confidence: 99%

A comprehensive analysis of somatic alterations in Chinese ovarian cancer patients

Zhang

Shi

Zhang

et al. 2021

Sci Rep

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Ovarian cancer is one of the most common cancers in women and is often diagnosed as advanced stage because of the subtle symptoms of early ovarian cancer. To identify the somatic alterations and new biomarkers for the diagnosis and targeted therapy of Chinese ovarian cancer patients, a total of 65 Chinese ovarian cancer patients were enrolled for detection of genomic alterations. The most commonly mutated genes in ovarian cancers were TP53 (86.15%, 56/65), NF1 (13.85%, 9/65), NOTCH3 (10.77%, 7/65), and TERT (10.77%, 7/65). Statistical analysis showed that TP53 and LRP1B mutations were associated with the age of patients, KRAS, TP53, and PTEN mutations were significantly associated with tumor differentiation, and MED12, LRP2, PIK3R2, CCNE1, and LRP1B mutations were significantly associated with high tumor mutational burden. The mutation frequencies of LRP2 and NTRK3 in metastatic ovarian cancers were higher than those in primary tumors, but the difference was not significant (P = 0.072, for both). Molecular characteristics of three patients responding to olapanib supported that BRCA mutation and HRD related mutations is the target of olaparib in platinum sensitive patients. In conclusion we identified the somatic alterations and suggested a group of potential biomarkers for Chinese ovarian cancer patients. Our study provided a basis for further exploration of diagnosis and molecular targeted therapy for Chinese ovarian cancer patients.

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Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition

Cited by 52 publications

References 64 publications

A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients

A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients

Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity

A comprehensive analysis of somatic alterations in Chinese ovarian cancer patients

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